Cells derived from wild mouse species and inbred laboratory mouse strains differ from one another in their susceptibility to the mouse gammaretroviruses and retrovirus-induced diseases. These differences are due to differences in specific host genes, and we have been engaged in an ongoing effort to identify and characterize several mouse genes involved in this resistance. Our major focus has been on cell surface virus receptors and cellular factors that interfere with receptor binding. One area of investigation focused on a novel virus resistance gene originally found in the wild mouse species M. castaneus. This gene, termed Rmcf2, is responsible for partial resistance to the highly pathogenic polytropic class of leukemia viruses. We have now demonstrated that this resistance is due to a chromosomally integrated copy of the viral genome, and we have shown that expression of the envelope glycoprotein of this integrated provirus is associated with the virus resistance phenotype. This suggests that Rmcf2 resistance may be mediated through an interference mechanism. A second study deals with two unusual variants of the ecotropic gammaretroviruses that are cytopathic in M. dunni cells and also have altered host range. These phenotypes are due to different amino acid substitutions at the same site in the two viruses. This substitution alters one of the 3 amino acids that form the cell surface receptor binding site. The fact that these 2 viruses cause cytopathic effects in a cell line with a variant receptor gene suggests that the virus-receptor interaction mediates cytopathicity. This conclusion was confirmed by the observation that cytopathicity due to virus infection is seen in stable transfectants expressing this variant receptor but not in transfectants expressing the prototypical receptor. Because evidence also suggests that cytopathicity is affected by inhibitors of glycosylation, we are currently evaluating the role of glycosylation in virus infectivity and cytopathicity. In a third study, we have screened a panel of cells derived from evolutionarily divergent wild mouse species for infectivity with a panel of mouse gammaretroviruses. These viruses use two different cell surface receptors and represent three distinct host range subtypes in laboratory mice. These viruses show novel patterns of infectivity in the wild mouse cells. Factors that contribute to the observed infectivity differences include receptor polymorphisms, differences in glycosylation, and variable levels of receptor expression.